Bicyclo[1.1.1]pentanes and their derivatives are structural motifs in many physiologically active compounds and therefore are used as key intermediates in their preparation. It was shown that in a number of cases, active molecules containing these derivatives show useful physico-chemical properties and that their use is sometimes superior to more standard fragments such as aromatic or lipophilic groups, making them potential bioisosters for phenyl or tert-butyl groups as postulated and/or demonstrated in the literature (e.g. M. R. Barbachyn et al. Bioorg. Med. Chem. Lett. 1993, 3, 671-676, A. F. Stepan et al. J. Med. Chem. 2012, 55, 3414-3424, K. D. Bunker et al. Org. Lett. 2011, 13, 4746-4748 and Y. L. Goh et al. Org. Lett. 2014, 16, 1884-1887).
Bicyclo[1.1.1]pentanes have been used as intermediates in the preparation of various compounds with different areas of application. Thus, the properties displayed by compounds containing bicyclo[1.1.1]pentanes are not limited to a particular medical indication (see for example FIG. 1 describing several physiologically active compounds that have been reported to benefit from the properties of the bicyclo[1.1.1]pentanes, such as fluoroquinolone antibiotics, JAK inhibitors or gamma-secretase inhibitors).
There is therefore an increasing interest in the area of life science as well as material sciences to access the most diverse set of bicyclo[1.1.1]pentane derivatives in large quantities in a time and cost efficient manner. However, the current process to make bicyclo[1.1.1]pentane derivatives is still tedious and requires several steps, especially for the synthesis of asymmetrically substituted derivatives, and often requires toxic reagents. To date two main approaches are known to access bicyclo[1.1.1]pentanes:
The first one requires the preparation of bicyclo[1.1.0]butanes followed by cyclopropanation with a carbene (:CCl2) and dechlorination, as reported by Applequist et al. J. Org. Chem. 1982, 4985-4995 (FIG. 2A). However, this synthesis uses toxic and/or expensive reagents and presents moderate yields.
The second approach is the most described synthesis in the prior art (Org. Synth. 1998, 75, 98; Org. Synth. 2000, 77, 249) in which the central bond of [1.1.1]propellane is reacted with a variety of reagents to form 1,3-disubstituted bicyclo[1.1.1]pentanes.
The scope of reagents and reactions mainly delivers symmetrical bicyclo[1.1.1]pentane derivatives, or asymmetrically substituted derivatives that are limited to substituents unsuitable for further derivatization. Furthermore, the yields are usually low to moderate and suffer from contamination with a number of by-products, principally due to polymerization and dimerization.
The synthesis of asymmetrical derivatives is in particular challenging and obtained products are usually in form of mixtures with by-products, regio-isomers or polymers.
One particular method (P. Kaszyncki, and J. Michl, J. Org. Chem. 1988, 53, 4594-4596) to access synthetically useful intermediates such as 1,3-disubstituted monoacid-monoesters consists in treating [1.1.1]propellane with buta-2,3-dione under irradiation to give the diketone intermediate (FIG. 2B). Subsequent haloform reaction, followed by di-ester formation and mono-saponification afforded the desymmetrized product. However, a total of 6 reaction steps are required with an overall yield varying between 20% and 40%, associated with problems of reproducibility and the need for repeated purifications at each step make this route very difficult in particular to perform on large scale.
Therefore, there is a need for a synthetically efficient route that could overcome the disadvantages of the methods in the prior art, which is also compatible with large-scale production using common reagents and minimal need for purification.
Applicants have now found a new, efficient, selective and versatile method for synthesizing a wide range of asymmetrically 1,3-disubstituted bicyclo[1.1.1]pentane intermediates and symmetrically and asymmetrically mono- and 1,3-disubstituted bicyclo[1.1.1]pentane derivatives thereof.